The primary aim of this project is to understand whether it is possible to reduce medical risk factors in adults with bipolar disorder and, in doing so, to improve psychiatric and functional outcomes. In response to PA-07- 211, Health Behavior Change in People with Mental Disorders, we will examine the role of behavioral risk factors and presumed behavioral mediators and moderators of health risk in individuals suffering from bipolar disorder. We will employ a multi-pronged, longitudinal treatment platform that integrates an innovative behavioral intervention with guideline based psychiatric care (Integrated Risk Reduction Intervention} IRRI) in order to target modifiable medical risk factors. IRRI is aimed at ameliorating sleep/wake and social rhythm disturbance and achieving modest weight reduction by increasing physical activity and improving nutrition and dietary habits, while at the same time providing optimal psychiatric care and medical monitoring. This will allow us to investigate the role that improvements in sleep/wake and social rhythm regularity, diet, and physical activity have in improving psychiatric and functional outcomes. In order to examine another set of possible pathways (i.e., that it is the amelioration of psychiatric symptoms that leads to improvements in physical health), we will contrast outcomes of subjects receiving IRRI with those of subjects receiving psychiatric care with medical monitoring (PCMM), which incorporates the same optimal psychiatric care plus monitoring of medical conditions. These aims will be achieved in a 24-month randomized treatment trial of 144 adult patients with bipolar disorder. We hypothesize that 1) IRRI compared with PCMM will result in a larger decrease in medical risk factors and greater improvement in sleep/wake and social rhythm disturbances; and 2) IRRI compared with PCMM will result in greater improvement in mood symptoms and functioning, particularly employment-related functioning. Our secondary hypotheses are that: 1) The effect of IRRI on improved mood symptoms and functioning will be mediated by the effect of IRRI on medical risk factors and on sleep/wake and social rhythm disturbances; 2) the effect of IRRI on medical risk factors and sleep/wake and social rhythm disturbances will be mediated by patients' regular participation and adherence; 3) High baseline medical risk factors will predict worse outcomes over the course of the study for patients receiving PCMM than for patients with similarly high baseline medical risk factors who receive IRRI; and 4) Higher within-subject variation in medical risk and sleep/wake and social rhythm disturbances over the course of the study will be associated with smaller decreases in medical risks, smaller improvements in sleep/wake and social rhythm disturbances, and smaller improvements in mood symptoms and functioning. Additionally, within-subject variation in medical risk parameters over the course of the study will be smaller in patients receiving IRRI than in those receiving PCMM. PUBLIC HEALTH RELEVANCE: The public health consequences of the morbidity and mortality associated with bipolar disorder are enormous and have increased over the past decade, despite the introduction of new pharmacological interventions. If we could better assess the risk and protective factors underlying the accumulation of psychiatric and medical morbidity in patients with bipolar disorder, then early interventions could be designed to prevent the rapid accumulation of chronic disease and adverse prognoses leading to persistent poor functioning and disability. We hope to identify such risk and protective factors, intervene to reduce medical risk factors with the expectation that psychiatric outcomes will be substantially improved, and thus provide a framework for further efforts at secondary prevention. [unreadable] [unreadable] [unreadable]